Resolving human α versus β cell fate allocation for the generation of stem cell-derived islets

ABSTRACT: Generating stem cell-derived glucagon-producing α and insulin-producing β cells allows to engineer in vitro biomimetics of the islet of Langerhans, the micro-organ controlling blood glucose; however, there is still a major knowledge gap in the mechanism by which human stem cell-derived α and β cells are specified. Mouse studies postulated that Aristaless Related homeobox (Arx) and Paired box 4 (Pax4) transcription factors cross-inhibit each other in endocrine progenitors to promote α or β cell fate allocation, respectively. To test this model in human, we generated an ARXCFP/CFP; PAX4mCherry/mCherry double knock-in reporter induced pluripotent stem cell line to combine time-resolved cell lineage labeling with high-resolution single cell multiomic analysis. Strikingly, lineage labelling and tracing, proteomic and gene regulatory network analysis and potency assays revealed a human specific regulation of α versus β cell fate allocation. Pharmacological perturbation using drugs previously proposed to trigger α-to-β cell transdifferentiation or identified via our gene regulatory network analysis led to enhanced endocrine induction and directed α versus β cell fate commitment. Thus, shedding light on basic mechanisms of endocrine induction and fate segregation not only paves the way to engineer islets from pluripotent stem cells, but has broader implications for cell-replacement therapy, disease modelling and drug screening.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hipsc Cell

SUBMITTER: Juliane Merl-Pham  

LAB HEAD: Heiko Lickert

PROVIDER: PXD064617 | Pride | 2026-05-19

REPOSITORIES: pride